Tandem Flavin-Iodine-Catalyzed Aerobic Oxidative Sulfenylation of Imidazo[1,2- a]Pyridines with Thiols

Article abstract of DOI:10.1021/acs.joc.8b01878

A green, aerobic sulfenylation of imidazo[1,2-a]pyridines was performed using thiols, a flavin-and-iodine dual catalytic system, and environmentally benign molecular oxygen as the only sacrificial reagent. The dual metal-free catalysts smoothly promote a unique stepwise tandem process, beginning with the aerobic oxidation of a thiol to afford a disulfide that is utilized in the oxidative sulfenylation of the imidazo[1,2-a]pyridine. This process has afforded diverse 3-sulfenylimidazo[1,2-a]pyridines of biological interest and is environmentally friendly, as benign H₂O is the only byproduct.

Full text of DOI:10.1021/acs.joc.8b01878

Subscriber access provided by UNIV OF DURHAM
Note
Tandem Flavin-Iodine-Catalyzed Aerobic Oxidative
Sulfenylation of Imidazo[1,2-a]Pyridines with Thiols
Hiroki Iida, Ryuta Demizu, and Ryoma Ohkado
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01878 • Publication Date (Web): 30 Aug 2018
Downloaded from http://pubs.acs.org on August 30, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 19
The Journal of Organic Chemistry
1
2
3
Tandem FlavinꢀIodineꢀCatalyzed Aerobic Oxidative Sulfenylation of
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Imidazo[1,2ꢀa]Pyridines with Thiols
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hiroki Iida*, Ryuta Demizu, and Ryoma Ohkado
Department of Chemistry, Graduate School of Natural Science and Technology, Shimane University,
1
060 Nishikawatsu, Matsue 690ꢀ8504, Japan
ABSTRACT: A green, aerobic sulfenylation of imidazo[1,2ꢀa]pyridines was performed using thiols, a
flavinꢀandꢀiodine dual catalytic system, and environmentally benign molecular oxygen as the only
sacrificial reagent. The dual metalꢀfree catalysts smoothly promote a unique stepwise tandem process,
beginning with the aerobic oxidation of a thiol to afford a disulfide that is utilized in the oxidative
sulfenylation
of
the
imidazo[1,2ꢀa]pyridine.
This
process
has
afforded
diverse
3
ꢀsulfenylimidazo[1,2ꢀa]pyridines of biological interest, and is environmentally friendly as benign H O
2
is the only byꢀproduct.
The construction of CꢀS bonds is a fundamental process in the synthesis of heteroaryl thioethers, and
their derivatives. The sulfenylation of imidazo[1,2ꢀa]pyridines has recently attracted increasing attention
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 19
as imidazo[1,2ꢀa]pyridines have been recognized as an important class of heterocyclic compounds that
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
are found in a wide range of bioactive pharmaceuticals and natural products. As shown in Figure. 1, the
imidazo[1,2ꢀa]pyridine scaffold is found in various biologically active compounds and commercially
2
2
3
3
available drugs like alpidem, zolpidem, nicopidem, saripidem (anxiolytic agent), zolimidine
4
5
6
(
gastroprotective agent), olprinone (cardiotonic agent), rifaximin (antibiotic), and GSK812397
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
(
treatment of HIV infection). Furthermore, imidazo[1,2ꢀa]pyridines possessing thio functionality have
been recognized as promising candidates for use in medicinal compounds. Indeed, this moiety has been
8
incorporated in medicinally active compounds such as anthelminthic, and an inhibitor of human
9
rhinovirus (Figure. 1). Therefore, various processes have been developed for the sulfenylation of
10
imidazo[1,2ꢀa]pyridines at C3, using a variety of reagents as the source of sulfur, such as a thiol,
11
8
12
13
14
15
disulfide,
sulfenyl chloride,
sulfonylchloride,
sulfinate,
sulfonothioate,
sulfoxide,
1
6
17
sulfonylhydrazide, and sulfur. Thiols are the simplest, most atomꢀeconomical, and readily available
of the sulfenylation reagents, as other reagents are often prepared from thiols and thus require additional
synthetic manipulations. However, the oxidative sulfenylation with thiols has been limited to a few
10a
10b
10d,e
methods using hypervalent iodine reagents, NCS, iodine catalysts with stoichiometric oxidants,
1
0c,f
10g
copper catalysts,
and photocatalysts. Unfortunately, these reagents have several drawbacks such as
the need for stoichiometric amounts of expensive sacrificial reagents, toxic metals, and photoirradiation.
The development of a novel, facile approach that fulfils the strong demand for green and sustainable
chemistry therefore remains an ongoing challenge.
Figure 1. Structures of medicinally active imidazo[1,2ꢀa]pyridines.
ACS Paragon Plus Environment
2

Page 3 of 19
The Journal of Organic Chemistry
1
2
3
4
There has been a recent demand for oxidative transformations with molecular oxygen, which can be
1
8
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
used as an atomꢀeconomical, easily available, and minimally polluting oxidant. Flavin catalysts, which
have been developed by mimicking the functions of flavinꢀdependent monooxygenases, have attracted
19,20
particular interest as these biomimetic organocatalysts are able to activate molecular oxygen.
Taking
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
inspiration from the enzymatic aerobic oxidation system, we recently developed a novel strategy for
2
1
green, oxidative transformations by coupling flavin and iodine catalysis. The dual catalytic system
21
successfully promoted aerobic oxidative thiadiazole ring formation of Nꢀtosylhydrazones with sulfur,
2
2
and then could be extended to the sulfenylation of indoles with thiols.
Herein, we present the flavinꢀiodineꢀcatalyzed, aerobic oxidative sulfenylation of
imidazo[1,2ꢀa]pyridines with thiols, proceeding in CH CN at 25 or 50 °C. This method offers a unique
3
green approach to the sulfenylation of this important class of compounds as, in addition to using the
dual nonꢀmetal catalytic system, the sulfenylation was promoted by molecular oxygen as the only
sacrificial reagent, yielding environmentally benign H O.
2
In the initial studies, the reaction conditions were optimized using 2ꢀphenylimidazo[1,2ꢀa]pyridine
(1a) and 4ꢀmethylbenzenethiol (2a, 1.2 equiv) in the presence of a range of flavin or cationic flavin
(
flavinium) catalysts (5 mol%) and I (5 mol%) at 50 °C under O atmosphere (Table 1, Figure 2).
2
2
Commercially available riboflavin (4a) and its tetraacetate (4b) failed to promote the sulfenylation
reaction (entries 1 and 2). The cationic flavin catalysts 5ꢀethylisoalloxazinium(5a•TfO and 5b•TfO),
5ꢀethylalloxazinium (6•TfO), and 1,10ꢀethyleneꢀbridged alloxazinium salts (7a•TfO and 7b•TfO),
which can be derived from 4a, were also investigated as these are known to display different redox and
2
3
catalytic properties which is dependent upon the πꢀconjugation of the ring structure. The results
showed that the success of the reaction was likely dependent upon the electrophilicity of the catalyst, as
the most electrophilic of the cationic catalysts 5a•TfO smoothly catalyzed the sulfenylation of 1a to
give the desired product 3a in 95% yield within 1 h; however, the less electrophilic catalysts 5b•TfO,
6
•TfO, 7a•TfO, and 7b•TfO showed poor to moderate catalytic activity (entries 3ꢀ7). Attempts using
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 19
various iodine sources such as I , TBAI, NH I, and KI showed that I gave the highest yield (Table S1,
2
4
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Supporting Information). Further optimization studies revealed that the sulfenylation proceeded in
2
4
excellent yield with only 2 mol% of 5a•TfO and 4 mol% of I in CH CN at 50 °C for 4 h (entry 8).
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 1. Optimization of the Sulfenylation of 1a with 2a
entry
flavin (mol%) I2 (mol%) time (h) yield (%)
1
2
3
4
5
6
7
4a (5)
4b (5)
5
5
5
5
5
5
5
4
1
1
1
1
1
1
1
4
4
4
4
<1
<1
94
84
41
10
12
95
1
5a•TfO (5)
5b•TfO (5)
6•TfO (5)
7a•TfO (5)
7b•TfO (5)
5a•TfO (2)
None
b
8
9
4
1
0
5a•TfO (2)
5a•TfO (2)
None
4
<1
<1
c
11
a
Conditions: 1a (0.5 M), 2a (0.6 M), flavin, I , and CH CN under O (1
2
3
2
b
atm) at 50 °C. Yield was determined by GC. 1a (1 M) and 2a (1.2 M)
were used. Under N .
c
2
Figure 2. Structures of riboflavin and riboflavinꢀderived catalysts.
ACS Paragon Plus Environment
4

Page 5 of 19
The Journal of Organic Chemistry
a
Table 2. Scope of Imidazo[1,2ꢀa]pyridines 1 and Thiols 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
Conditions: 1 (1 M), 2 (1.2 M), 5a•TfO (2 mol%), I (4 mol%), and CH CN under O (1 atm) at 50 °C for 4 h. 5a•TfO (5
2
3
2
c
d
1
e
mol%) and I (10 mol%) were used. At 25 °C. Yield was determined by H NMR using an internal standard. Under air (1
2
atm).
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 19
Having optimized the conditions on the model system, the substrate scope of the reaction was
investigated using a diverse range of imidazo[1,2ꢀa]pyridines 1 and thiols 2 (Table 2). Under these
conditions, imidazo[1,2ꢀa]pyridines bearing either electronꢀdonating or electronꢀwithdrawing groups on
the phenyl ring (3a–c) successfully underwent sulfenylation. In addition, imidazo[1,2ꢀa]pyridines with
substituents at the 6, 7, and 8 positions successfully reacted to yield the corresponding 3ꢀsulfenylated
products (3d-f). The sulfenylation of electronꢀdeficient imidazo[1,2ꢀa]pyridines bearing ester and cyano
groups was also performed (3g,h). A diverse range of thiols (3i-l) was then investigated and, to our
delight, the hydroxy and amino functionalities were compatible with the optimized reaction conditions
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(3k,l). Thiols possessing benzyl and alkyl substituents also proceeded in good yield, although 5 mol% of
5a•TfO and 10 mol% of I2 were required (3m,n). The sulfenylation of 2ꢀunsubstituted
imidazo[1,2ꢀa]pyridines occurred chemoselectively to give the 3ꢀsulfenylated products in 68ꢀ70% yields
(3o-q). It is noteworthy that the reaction could be performed at 25 °C (3a,f,i), whereas the previous
catalytic sulfenylations of imidazo[1,2ꢀa]pyridines with thiols had required heating conditions or
1
0cꢀg
photoirradiation.
Air could be utilized instead of pure O as an oxidant although a higher catalyst
2
loading and longer reaction time was required, as might be expected (3a).
To establish the mechanism of the reaction, control experiments were conducted. In stark contrast to
the reaction under the optimized conditions, the sulfenylation did not proceed in the absence of 5a•TfO,
I2, or molecular oxygen (Table 1, entries 9ꢀ11). The disulfide 8a could be used instead of the thiol 2a, as
indicated by the flavinꢀiodineꢀcatalysed sulfenylation of 1a with 8a which proceeded smoothly (Scheme
1A). To gain further insight into the mechanism, the sulfenylation of 1a with 2a was studied by GC
monitoring the timeꢀcourse of the yield and conversion (Figure 3). During the sulfenylation with 2a, 2a
was almost completely converted to 8a within the first hour. Interestingly, the conversion of 1a to 3a
only commenced once the thiol 2a had been completely oxidized to 8a, indicating that the sulfenylation
proceeds via the disulfide. Based on these results, the following tandem process that progresses in a
stepwise manner was proposed: (i) the aerobic oxidative transformation of the thiol 2a to the disulfide
8
a followed by (ii) the aerobic oxidative sulfenylation of 1a with 8a (Scheme 2A). In scheme 1B and C,
ACS Paragon Plus Environment
6

Page 7 of 19
The Journal of Organic Chemistry
two control experiments are shown in which the flavin catalyst was omitted from the sulfenylation
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction of 2a or 8a. Even in the presence of a large excess of I (300 mol%), the direct sulfenylation of
2
1a with 2a hardly progressed; however, I promoted the oxidation of 2a to 8a (Scheme 1B). The
2
reaction of 1a with 8a in the presence of 300 mol% of I gave the sulfenylated product 3a although in a
2
modest yield (Scheme 1C). These results clearly revealed the need for both the flavin and I catalysts, i.e.
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the dual catalytic system presented herein.
Scheme 1. Control Experiments
The most plausible reaction mechanism for the flavinꢀiodineꢀcatalyzed aerobic sulfenylation of
imidazo[1,2ꢀa]pyridines 1 with thiols 2 has been proposed, on the basis of the experimental results and
previous reports (Scheme 2B). The thiol 2 is converted to the disulfide 8, by the flavinꢀcatalyzed aerobic
2
2,25
oxidation reaction and the oxidation with I2.
The disulfide 8 then reacts with I to provide RꢀSI,
2
–
+ 10d,e
which undergoes nucleophilic attack by 1 to yield the desired product 3 along with I and H .
The
–
+
flavin organocatalyst 5a efficiently promotes the catalytic oxidation of I and H to regenerate I and the
2
byꢀproduct H O, respectively, via the formation of the reduced flavin (5a ) and 4aꢀhydroperoxyflavin
2
red
2
1
(5aOOH). Although the oxidative generation of disulfides and the sulfenylation of substrates occurs
2
2
simultaneously in the previously reported aerobic sulfenylation of indoles, the present process
progresses the tandem process in a stepwise manner (Scheme 2A). Through the oxidative generation of
+
H O, the present dual catalytic system can remove in situꢀgenerated H which would otherwise cause
2
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 19
sideꢀreactions that inhibit the sulfenylation and thus, presumably results in the efficient sulfenylation
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with thiols. Indeed, this would explain the poor results obtained when only I was utilized, even if in
2
large excess (Scheme 1B).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Timeꢀcourse of the sulfenylation of 1a (0.2 M) with 2a (1.2 equiv) carried out in CH CN in
3
the presence of 5a•TfO (2 mol%) and I (4 mol%) under molecular oxygen (1 atm) at 50 °C.
2
ACS Paragon Plus Environment
8

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
Scheme 2. (A) Scheme for the Stepwise Tandem Process of the Present Oxidative Sulfenylation. (B)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Proposed Mechanism for the Coupled FlavinꢀIodine Organocatalysis
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In conclusion, we have developed an efficient strategy for the regioselective Cꢀ3 sulfenylation of
imidazo[1,2ꢀa]pyridines with thiols, using a metalꢀfree dual catalytic system consisting of a
riboflavinꢀderived organocatalyst and an iodine catalyst. This methodology enables O ꢀdriven
2
sulfenylation in the absence of stoichiometric amounts of expensive sacrificial reagents, toxic metals,
and photoirradiation, and thus provides attractive green sulfenylation chemistry to access biologically
important 3ꢀsulfenylimidazo[1,2ꢀa]pyridines.
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 19
Experimental Section
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
General Information. The NMR spectra were measured using JEOL JNMꢀL400 and JNM
1
ECXꢀ500 spectrometers (JEOL, Akishima, Japan) operating at 400 and 500 MHz, respectively, for H
1
3
and 100 and 126 MHz, respectively, for C using tetramethylsilane (TMS) or a solvent residual peak as
the internal standard. The electrospray ionization mass (ESIꢀMS) spectra were recorded using a Bruker
microTOFIIꢀSHIY3 mass spectrometer (Bruker, Billerica, MA). The GC measurements were performed
on a Shimadzu GCꢀ2014 gas chromatograph (Shimadzu, Kyoto, Japan) equipped with a flame
ionization detector (FID) using Supelco Equityꢀ5 (30 m x 0.25 mm) column.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
All starting materials were purchased from Aldrich (Milwaukee, WI), Wako Pure Chemical Industries
(Osaka, Japan), and Tokyo Kasei (TCI, Tokyo, Japan) and were used as received. Riboflavin
2
6
23
tetraacetate (4b),
5ꢀethylꢀ10ꢀ(2ꢀhydroxylethyl)ꢀ7,8ꢀdimethylisoalloxazinium triflate (5a•TfO),
23
5
5
ꢀethylꢀ10ꢀ(2ꢀhydroxylethyl)ꢀ3,7,8ꢀtrimethylisoalloxazinium triflate (5b•TfO),
23
ꢀethylꢀ1,3,7,8ꢀtetramethylalloxazinium triflate (6•TfO),
1,10ꢀethyleneꢀ7,8ꢀdimethylalloxazinium
2
3
23
triflate (7a•TfO), and 1,10ꢀethyleneꢀ3,7,8ꢀtrimethylalloxazinium triflate (7b•TfO) were synthesized
according to the previously reported methods.
Typical Procedure for Catalytic Sulfenylation of 1a with 2a in the Presence of 5a•TfO and I . A
2
mixture of 1a (194 mg, 1.0 mmol), 2a (149 mg, 1.2 mmol), I (10.2 mg, 0.040 mmol), 5a•TfO (9.28
2
mg, 0.020 mmol), and CH CN (1.0 mL) was stirred at 50 ˚C for 4 h under O . After an addition of water
3
2
(30 mL), the mixture was extracted with CHCl (30 mL x 3), and the organic layer was washed with
3
water (30 mL), dried over anhydrous MgSO , and filtered. After the solvent was removed by
4
evaporation, the residue was purified by column chromatography (SiO , hexane/ethyl acetate = 5/1 to
2
2/1, v/v) to give 3a (294 mg, 93%) as a white solid. These results are summarized in Table 2.
1
0e 1
Spectroscopic data of 3a : H NMR (500 MHz, CDCl , 25 ˚C): δ 8.27 (d, J = 6.9 Hz, 1H), 8.22 (d, J =
3
7
6
.2 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.31 (dd, J = 9.1,
13
.7 Hz, 1H), 7.01 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.2 Hz, 2H), 6.85 (t, J = 6.4 Hz, 1H), 2.25 (s, 3H). C
NMR (126 MHz, CDCl , 25 ˚C): δ 151.4, 147.2, 136.2, 133.6, 131.6, 130.3, 128.7, 128.5, 128.5, 126.7,
3
125.9, 124.7, 117.8, 113.1, 107.0, 21.0.
1
0e
Spectroscopic data of 3b : Column chromatography (SiO , hexane/ethyl acetate = 100/0 to 4/1, v/v)
2
1
afforded the desired product (122 mg, 88%) as a white solid. H NMR (500 MHz, CDCl , 25 ˚C): δ 8.26
3
(d, J = 6.8 Hz, 1H), 8.18 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.33ꢀ7.27 (m, 1H), 7.01 (d, J =
8
.2 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.83 (t, J = 6.8 Hz, 1H), 3.83 (s, 3H),
ACS Paragon Plus Environment
10

Page 11 of 19
The Journal of Organic Chemistry
1
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2.25 (s, 3H). C NMR (126 MHz, CDCl , 25 ˚C): δ 160.1, 151.3, 147.1, 136.1, 131.8, 130.3, 129.8,
3
1
26.5, 126.2, 125.9, 124.6, 117.5, 114.0, 112.9, 106.0, 55.4, 21.0.
10e
Spectroscopic data of 3c : Column chromatography (SiO , hexane/ethyl acetate = 100/0 to 4/1, v/v)
2
1
afforded the desired product (121 mg, 86%) as a beige solid. H NMR (500 MHz, CDCl , 25 ˚C): δ 8.28
3
(
d, J = 6.9 Hz, 1H), 8.19 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.33 (dd,
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 9.1, 6.8 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.90ꢀ6.85 (m, 3H), 2.26 (s, 3H). C NMR (126 MHz,
CDCl , 25 ˚C): δ 150.1, 147.2, 136.4, 134.7, 132.1, 131.3, 130.4, 129.7, 128.8, 126.9, 126.0, 124.7,
3
1
17.8, 113.3, 107.2, 21.0.
13c
Spectroscopic data of 3d : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
1
afforded the desired product (119 mg, 90%) as a pale yellow solid. H NMR (500 MHz, CDCl , 25 ˚C):
3
δ 8.20 (d, J = 7.2 Hz, 2H), 8.06 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.4
Hz, 1H), 7.13 (dd, J = 9.5, 1.7 Hz, 1H), 7.00 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.3 Hz, 2H), 2.27 (s, 3H),
1
3
2.24 (s, 3H). C NMR (126 MHz, CDCl , 25 ˚C): δ 151.1, 146.1, 135.9, 133.7, 132.0, 130.2, 129.7,
3
1
28.44, 128.41, 128.3, 125.7, 122.9, 122.3, 117.0, 106.3, 20.9, 18.4.
13c
Spectroscopic data of 3e : This compound was purified by column chromatography (SiO ,
2
1
hexane/ethyl acetate = 5/1 to 2/1, v/v) afforded the desired product (105 mg, 80%) as a white solid. H
NMR (500 MHz, CDCl , 25 ˚C): δ = 8.20 (d, J = 7.3 Hz, 2H), 8.11 (d, J = 7.0 Hz, 1H), 7.46 (s, 1H),
3
7.41 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 6.64
1
3
(d, J = 7.0 Hz, 1H), 2.40 (s, 3H), 2.23 (s, 3H). C NMR (126 MHz, CDCl , 25 ˚C): δ 151.2, 147.5,
3
1
37.8, 136.0, 133.7, 131.9, 130.2, 128.5, 128.42, 128.37, 125.8, 123.7, 116.2, 115.6, 106.0, 21.5, 20.9.
13c
Spectroscopic data of 3f : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
1
afforded the desired product (121 mg, 91%) as a white solid. H NMR (500 MHz, CDCl , 25 ˚C): δ 8.20
3
(
d, J = 7.3 Hz, 2H), 8.11 (d, J = 6.7 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.06 (d, J
= 6.9 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.72 (t, J = 6.8 Hz, 1H), 2.69 (s, 3H),
1
3
2.23 (s, 3H). C NMR (126 MHz, CDCl , 25 ˚C): δ 150.9, 147.4, 135.9, 133.8, 131.9, 130.2, 129.9,
3
1
28.6, 128.5, 127.7, 125.9, 125.4, 122.4, 113.0, 107.1, 21.0, 16.9.
10e
Spectroscopic data of 3g : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
1
afforded the desired product (134 mg, 89%) as a beige solid. H NMR (500 MHz, CDCl , 25 ˚C): δ 9.05
3
(
s, 1H), 8.24 (d, J = 7.2 Hz, 2H), 7.87 (dd, J = 9.4, 1.7 Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.45 (t, J = 7.4
Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 3.92 (s, 3H), 2.26 (s,
1
3
3H). C NMR (126 MHz, CDCl , 25 ˚C): δ 165.3, 152.8, 147.7, 136.6, 133.0, 131.2, 130.4, 129.1,
3
1
28.6, 128.5, 126.4, 126.3, 117.2, 117.1, 108.8, 52.6, 21.0.
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 19
1
7b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Spectroscopic data of 3h : Column chromatography (SiO , hexane/ethyl acetate = 100/1 to 4/1, v/v)
2
1
afforded the desired product (99.4 mg, 76%) as a white solid. H NMR (500 MHz, CDCl , 25 ˚C): δ
3
8
2
1
.66 (s, 1H), 8.23 (d, J = 7.0 Hz, 2H), 7.75 (d, J = 9.2 Hz, 1H), 7.53ꢀ7.36 (m, 4H), 7.23 (t, J = 7.5 Hz,
13
H), 7.17 (t, J = 7.3 Hz, 1H), 7.00 (d, J = 8.2 Hz, 2H). C NMR (126 MHz, CDCl , 25 ˚C): δ 153.3,
3
46.3, 133.6, 132.3, 130.5, 129.9, 129.5, 128.7, 128.5, 126.9, 126.6, 126.0, 118.6, 116.5, 108.7, 99.3.
1
3c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Spectroscopic data of 3i : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
1
afforded the desired product (109 mg, 91%) as a white solid. H NMR (500 MHz, CDCl , 25 ˚C): δ 8.25
3
(
d, J = 6.9 Hz, 1H), 8.21 (d, J = 7.4 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.36 (t, J
=
7.4 Hz, 1H), 7.34ꢀ7.28 (m, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 7.9 Hz,
13
2
1
H), 6.84 (t, J = 6.8 Hz, 1H); C NMR (126 MHz, CDCl , 25 ˚C): δ 151.4, 147.1, 135.2, 133.4, 129.5,
3
28.6, 128.4, 128.4, 126.7, 126.1, 125.6, 124.5, 117.7, 113.1, 106.3.
1
3c
Spectroscopic data of 3j : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 1/1, v/v)
2
1
afforded the desired product (112 mg, 83%) as a white solid. H NMR (500 MHz, CDCl , 25 ˚C): δ 8.21
3
(
d, J = 6.8 Hz, 1H), 8.18 (d, J = 7.4 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.37 (t, J
=
7.4 Hz, 1H), 7.34ꢀ7.29 (m, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.86 (t, J = 6.8 Hz,
13
1
1
H); C NMR (126 MHz, CDCl , 25 ˚C): δ 151.7, 147.3, 133.8, 133.3, 132.1, 129.6, 128.8, 128.5,
3
28.4, 126.9, 124.4, 117.8, 113.3, 105.8.
17b
Spectroscopic data of 3k : Column chromatography (SiO , CHCl /MeOH = 100/0 to 40/1, v/v)
2
3
1
afforded the desired product (108 mg, 85%) as a white solid. H NMR (500 MHz, DMSOꢀd , 25 ˚C): δ
6
9
.58 (s, 1H), 8.47 (d, J = 6.8 Hz, 1H), 8.26ꢀ8.20 (m, 2H), 7.73 (d, J = 9.0 Hz, 1H), 7.54ꢀ7.33 (m, 4H),
13
7
.06 (t, J = 6.8 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H); C NMR (126 MHz,
DMSOꢀd , 25 ˚C): δ 156.8, 149.1, 146.1, 133.4, 128.6, 128.5, 128.4, 127.9, 127.1, 124.6, 122.4, 117.2,
6
1
16.8, 113.6, 107.8.
Spectroscopic data of 3l: Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
–1
afforded the desired product (98.2 mg, 77%) as a pale green solid. MP: 185.7ꢀ186.9 ˚C. IR (KBr, cm ):
1
3
1
7
=
408, 3067, 3017, 1631, 1478, 1344, 736. H NMR (500 MHz, CDCl , 25 ˚C): δ 8.33 (d, J = 6.9 Hz,
3
H), 8.21 (d, J = 7.3 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H),
.31ꢀ7.25 (m, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.86 (t, J = 6.8 Hz, 1H), 6.63 (d, J
1
3
8.0 Hz, 1H), 6.55 (t, J = 7.6 Hz, 1H), 4.00 (s, 2H); C NMR (126 MHz, CDCl , 25 °C): δ 151.0,
3
147.0, 145.9, 133.7, 130.6, 128.8, 128.8, 128.7, 128.6, 126.5, 124.8, 119.2, 117.8, 116.7, 116.1, 113.1,
+
106.9. HRMS (ESI+): m/z calculated for C H N S (M +H ), 318.1059; found, 318.1062.
1
9
16
3
ACS Paragon Plus Environment
12

Page 13 of 19
The Journal of Organic Chemistry
1
7c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Spectroscopic data of 3m : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 1/1, v/v)
2
1
afforded the desired product (101 mg, 80%) as a pale yellow oil. H NMR (500 MHz, CDCl , 25 ˚C): δ
3
8
.24 (d, J = 7.8 Hz, 2H), 8.06 (d, J = 6.9 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.37
(
t, J = 7.3 Hz, 1H), 7.20ꢀ7.14 (m, 1H), 7.10ꢀ6.99 (m, 3H), 6.91 (d, J = 7.5 Hz, 2H), 6.64 (t, J = 6.8 Hz,
1
3
1
H), 3.80 (s, 2H); C NMR (126 MHz, CDCl , 25 °C): δ 150.3, 146.5, 137.2, 133.9, 128.8, 128.5,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
128.4, 128.3, 127.4, 126.0, 124.3, 117.4, 112.3, 109.4, 40.7.
Spectroscopic data of 3n: Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
–
1
afforded the desired product (114 mg, 85%) as a white solid. MP: 43.2ꢀ44.5 ˚C. IR (KBr, cm ): 3032,
1
2
8
7
953, 2926, 2854, 1465, 1346, 758, 698. H NMR (500 MHz, CDCl , 25 ˚C): δ 8.49 (d, J = 6.9 Hz, 1H),
3
.31 (d, J = 7.3 Hz, 2H), 7.65 (d, J = 9.0 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H),
.29ꢀ7.23 (m, 1H), 6.89 (t, J = 6.7 Hz, 1H), 2.63 (t, J = 7.2 Hz, 2H), 1.41 (quin, J = 7.4 Hz, 2H),
1
3
1.31ꢀ1.04 (m, 10H), 0.85 (t, J = 7.2 Hz, 3H). C NMR (126 MHz, CDCl , 25 °C): δ 149.7, 146.5, 134.1,
3
128.5, 128.4, 128.2, 125.8, 124.5, 117.7, 112.6, 110.5, 35.8, 31.8, 29.5, 29.15, 29.12, 28.6, 22.7, 14.2.
+
HRMS (ESI+): m/z calculated for C H N S (M +H ), 339.1889; found, 339.1889.
2
1
27
2
13c
Spectroscopic data of 3o : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
1
afforded the desired product (65.3 mg, 68%) as a white solid. H NMR (500 MHz, CDCl , 25 ˚C): δ
3
8
.20 (d, J = 6.8 Hz, 1H), 7.97 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.28 (dd, J = 8.9, 7.0 Hz, 1H), 7.01 (d, J
1
3
= 8.1 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.84 (t, J = 6.4 Hz, 1H), 2.45 (s, 3H); C NMR (126 MHz,
CDCl , 25 °C): δ 148.0, 142.2, 136.4, 131.5, 130.1, 126.7, 125.9, 124.4, 118.2, 113.1, 111.5, 21.0.
3
17b
Spectroscopic data of 3p : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
1
afforded the desired product (64.8 mg, 70%) as a pale yellow solid. H NMR (500 MHz, CDCl , 25 ˚C):
3
δ 8.21 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.30 (dd, J = 9.2, 6.8 Hz, 1H), 7.20 (t,
13
J = 7.5 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.3 Hz, 2H), 6.87 (t, J = 6.5 Hz, 1H); C NMR
(126 MHz, CDCl , 25 °C): δ 148.2, 142.5, 135.3, 129.4, 126.30, 126.27, 126.1, 124.4, 118.2, 113.3,
3
110.8.
13c
Spectroscopic data of 3q : Column chromatography (SiO , hexane/ethyl acetate = 5/1 to 2/1, v/v)
2
1
afforded the desired product (72.0 mg, 68%) as a pale yellow solid. H NMR (500 MHz, CDCl , 25 ˚C):
3
δ 8.17 (d, J = 6.9 Hz, 1H), 7.99 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.32 (dd, J = 9.2, 6.8 Hz, 1H), 7.17 (d,
1
3
J = 8.6 Hz, 2H), 6.96ꢀ6.85 (m, 3H); C NMR (126 MHz, CDCl , 25 °C): δ 148.3, 142.7, 133.8, 132.3,
3
129.5, 127.5, 126.3, 124.2, 118.3, 113.4, 110.2.
ASSOCIATED CONTENT
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 19
Supporting Information
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The Supporting Information is available free of charge on the ACS Publications website.
Data for the optimization of reaction condition and NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Author
Eꢀmail: iida@riko.shimaneꢀu.ac.jp
ORCID
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hiroki Iida: 0000ꢀ0002ꢀ7114ꢀ0364
ACKNOWLEDGMENT
This work was supported in part by JSPS KAKENHI (GrantꢀinꢀAid for Scientific Research
(C), no. 16K05797) and the Shorai Foundation for Science and Technology. This work was
performed in part under the Cooperative Research Program of the Institute for Protein Research,
Osaka University, CRꢀ17ꢀ05.
REFERENCES
(1) For reviews, see: (a) EnguehardꢀGueiffier, C.; Gueiffier, A. Recent Progress in the Pharmacology
of Imidazo[1,2ꢀa]pyridines. Mini. Rev. Med. Chem. 2007, 7, 888. (b) Couty, F.; Evano, G. I. in
Comprehensive Heterocyclic Chemistry III; Vol. 11, eds. Katritzky, A. R.; Ramsden, C. A.; Scriven, E.
F. V.; Taylor, R. J. K.; Elsevier, Amsterdam 2008 pp. 409. (c) Koubachi, J.; El Kazzouli, S.; Bousmina,
M.; Guillaumet, G. Functionalization of Imidazo[1,2‐a]pyridines by Means of Metal‐Catalyzed Cross‐
Coupling Reactions. Eur. J. Org. Chem. 2014, 2014, 5119. (d) Bagdi, A. K.; Santra, S.; Monir, K.;
Hajra, A. Synthesis of Imidazo[1,2‐a]pyridines: a Decade Update. Chem. Commun. 2015, 51, 1555. (e)
Ravi, C.; Adimurthy, S. Synthesis of Imidazo[1,2‐a]pyridines: CꢀH Functionalization in the Direction of
CꢀS Bond Formation. Chem. Rec. 2017, 17, 1019.
ACS Paragon Plus Environment
14

Page 15 of 19
The Journal of Organic Chemistry
(
2) Langer, S. Z.; Arbilla, S.; Benavides, J.; Scatton, B. Zolpidem and Alpidem: Two
1
2
Imidazopyridines with Selectivity for Omegaꢀ1ꢀreceptor and Omegaꢀ3ꢀreceptor Subtypes. Adv.
Biochem. Psychopharmacol. 1990, 46, 61.
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
3) Boerner, R. J.; Moller, H. J. Saripidem ꢀ A New Treatment for Panic Disorders.
Psychopharmakotherapie 1997, 4, 145.
4) Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli, P.; Biancotti, A.; Gamba, A.;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Murmann, W. Derivatives of Imidazole . I. Synthesis and Reactions of Imidazo[1,2ꢀa]pyridienes with
Analgesic Antiinflammatory Antipyretic and Anticonvulsant Activity. J. Med. Chem. 1965, 8, 305.
(
5) Mizushige, K.; Ueda, T.; Yukiiri, K.; Suzuki, H. Olprinone: A Phosphodiesterase III Inhibitor with
Positive Inotropic and Vasodilator Effects. Cardiovasc. Drug Rev. 2002, 20, 163.
6) Scott, L. J. Rifaximin: A Review of Its Use in Reducing Recurrence of Overt Hepatic
(
Encephalopathy Episodes. Drugs 2014, 74, 2153.
(7) Gudmundsson, K.; Boggs, S. D. PCT Int. Appl. WO 2006026703, 2006.
(
8) Bochis, R. J.; Olen, L. E.; Fisher, M. H.; Reamer, R. A.; Wilks, G.; Taylor, J. E.; Olson, G.
Isomeric Phenylthioimidazo[1,2ꢀa]pyridines as Anthelmintics. J. Med. Chem. 1981, 24, 1483.
9) Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B. A.; Vance, L.
ꢀAminoꢀ3ꢀsubstitutedꢀ6ꢀ(E)ꢀ1ꢀphenylꢀ2ꢀ(Nꢀmethylcarbamoyl)vinyl Imidazoꢀ[1,2ꢀa]pyridines as a
(
2
Novel Class of Inhibitors of Human Rhinovirus: Stereospecific Synthesis and Antiviral Activity. J. Med.
Chem. 1999, 42, 50.
(10) (a) Hamdouchi, C.; Sanchez, C.; Ezquerra, J. Chemoselective Arylsulfenylation of
2
ꢀSminoimidazo[1,2ꢀa]pyridines by Phenyliodine(III) Bis(trifluoroacetate) (PIFA). Synthesis 1998, 867.
(
b) Ravi, C.; Mohan, D. C.; Adimurthy, S. NꢀChlorosuccinimideꢀpromoted Regioselective Sulfenylation
of Imidazoheterocycles at Room Temperature. Org. Lett. 2014, 16, 2978. (c) Zheng, Z. S.; Qi, D. Y.;
Shi, L. Copperꢀcatalyzed Thiolation of Imidazo[1,2ꢀa]pyridines with (Hhetero)aryl Thiols Using
Molecular Oxygen. Catal. Commun. 2015, 66, 83. (d) Yan, K. L.; Yang, D. S.; Sun, P. F.; Wei, W.; Liu,
Y.; Li, G. Q.; Lu, S. L.; Wang, H. Direct Thiolation of Methoxybenzenes with Thiols under MetalꢀFree
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 19
Conditions by Iodine Catalysis. Tetrahedron Lett. 2015, 56, 4792. (e) Hiebel, M.ꢀA.; BerteinaꢀRaboin,
S. Iodineꢀcatalyzed Regioselective Sulfenylation of Imidazoheterocycles in PEG(400). Green Chem.
2015, 17, 937. (f) Cao, H.; Chen, L. B.; Liu, J. Y.; Cai, H. Y.; Deng, H.; Chen, G. J.; Yan, C. J.; Chen,
Y. Regioselective CopperꢀCatalyzed Thiolation of Imidazo[1,2ꢀa]pyridines: An efficient CꢀH
Functionalization Strategy for CꢀS Bond Formation. RSC Adv. 2015, 5, 22356. (g) Rahaman, R.; Das,
S.; Barman, P. Green Chem. 2018, 20, 141.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(11) (a) Hamdouchi, C.; de Blas, J.; Ezquerra, J. A Novel Application of the Ullmann Coupling
Reaction for the Alkylsulfenylation of 2ꢀAminoꢀimidazo[1,2ꢀa]pyridine. Tetrahedron 1999, 55, 541. (b)
Li, Z.; Hong, J. Q.; Zhou, X. G. An Efficient and Clean CuIꢀCatalyzed Chalcogenylation of Aromatic
Azaheterocycles with Dichalcogenides. Tetrahedron 2011, 67, 3690. (c) Ge, W.; Zhu, X.; Wei, Y.
Aerobic Multicomponent Tandem Synthesis of 3ꢀSulfenylimidazo[1,2ꢀa]pyridines from Ketones,
2
ꢀAminopyridines, and Disulfides. Eur. J. Org. Chem. 2013, 2013, 6015. (d) Mohan, D. C.; Rao, S. N.;
Ravi, C.; Adimurthy, S. Copper( I) Iodide Catalyzed Aerobic Oxidative CꢀN and CꢀS Bond Formations
through CꢀH Activation: Synthesis of Functionalized Imidazo[1,2ꢀa]pyridines. Asian J. Org. Chem.
2
014, 3, 609. (e) Gao, Z. C.; Zhu, X.; Zhang, R. H. Cs CO Promoted Direct CꢀH Bond Sulfenylation of
2 3
Imidazo[1,2ꢀa]pyridines and Related Heteroarenes in Ionic Liquid. RSC Adv. 2014, 4, 19891. (f) Ji,
X.ꢀM.; Zhou, S.ꢀJ.; Chen, F.; Zhang, X.ꢀG.; Tang, R.ꢀY. Direct Sulfenylation of Imidazoheterocycles
with Disulfides in an Iodine–Hydrogen Peroxide System. Synthesis 2015, 47, 659. (g) Rafique, J.; Saba,
S.; Rosario, A. R.; Braga, A. L. Regioselective, Solventꢀ and MetalꢀFree Chalcogenation of
Imidazo[1,2ꢀa]pyridines by Employing I /DMSO as Catalytic Oxidation System. Chem. ꢀ Eur. J. 2016,
2
2
2, 11854. (h) Maddi, R. R.; Shirsat, P. K.; Kumar, S.; Meshram, H. M. NꢀBromosuccinimide Promoted
Direct Thiolation of Imidazoheteroaryl CꢀH bonds with Disulfides. Chemistryselect 2017, 2, 1544.
(12) (a) Ravi, C.; Mohan, D. C.; Adimurthy, S. Dual Role of pꢀTosylchloride: CopperꢀCatalyzed
Sulfenylation and Metal Free Methylthiolation of Imidazo[1,2ꢀa]pyridines. Org. Biomol. Chem. 2016,
1
4, 2282. (b) Wang, D.; Guo, S.; Zhang, R.; Lin, S.; Yan, Z. TBAIꢀHbr System Mediated Generation of
Various Thioethers with Benzenesulfonyl Chlorides in PEG(400). RSC Adv. 2016, 6, 54377.
ACS Paragon Plus Environment
16

Page 17 of 19
The Journal of Organic Chemistry
(
13) (a) Huang, X.; Wang, S.; Li, B.; Wang, X.; Ge, Z.; Li, R. IodineꢀTriphenylphosphine Mediated
1
2
Sulfenylation of Imidazoheterocycles with Sodium Sulfinates. RSC Adv. 2015, 5, 22654. (b) Ding, Y.;
Wu, W.; Zhao, W.; Li, Y.; Xie, P.; Huang, Y.; Liu, Y.; Zhou, A. Generation of Thioethers via Direct
CꢀH Functionalization with Sodium Benzenesulfinate as a Sulfur Source. Org. Biomol. Chem. 2016, 14,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
428. (c) Sun, P.; Yang, D.; Wei, W.; Jiang, M.; Wang, Z.; Zhang, L.; Zhang, H.; Zhang, Z.; Wang Y.;
Wang, H. Visible LightꢀInduced CꢀH Sulfenylation using Sulfinic Acids. Green Chem., 2017, 19, 4785.
14) Ravi, C.; Joshi, A.; Adimurthy, S. C3 Sulfenylation of NꢀHeteroarenes in Water under
CatalystꢀFree Conditions. Eur. J. Org. Chem. 2017, 2017, 3646.
15) Patil, S. M.; Kulkarni, S.; Mascarenhas, M.; Sharma, R.; Roopan, S. M.; Roychowdhury, A.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
DMSOꢀPOCl : A Reagent for Methylthiolation of Imidazo[1,2ꢀa]pyridines and other ImidazoꢀFused
3
Heterocycles. Tetrahedron 2013, 69, 8255.
(16) (a) Li, X.; Xu, Y.; Wu, W.; Jiang, C.; Qi, C.; Jiang, H. CopperꢀCatalyzed Aerobic Oxidative NꢀS
Bond Functionalization for CꢀS Bond Formation: Regioꢀand Stereoselective Synthesis of Sulfones and
Thioethers. Chem. ꢀ Eur. J. 2014, 20, 7911. (b) Bagdi, A. K.; Mitra, S.; Ghosh, M.; Hajra, A.
IodineꢀCatalyzed Regioselective Thiolation of Imidazo[1,2ꢀa]pyridines using Sulfonyl Hydrazides as a
Thiol Surrogate. Org. Biomol. Chem. 2015, 13, 3314.
(17) (a) Li, J. X.; Li, C. S.; Yang, S. R.; An, Y. N.; Wu, W. Q.; Jiang, H. F. PalladiumꢀCatalyzed
Oxidative Sulfenylation of Indoles and Related ElectronꢀRich Heteroarenes with Aryl Boronic Acids
and Elemental Sulfur. J. Org. Chem. 2016, 81, 7771. (b) Xiao, G.; Min, H.; Zheng, Z.; Deng, G. Liang,
Y. CopperꢀCatalyzed ThreeꢀComponent Reaction of Imidazo[1,2ꢀa]pyridine with Elemental Sulfur and
Arylboronic Acid to Produce Sulfenylimidazo[1,2ꢀa]pyridines. Chinese Chem. Lett., 2018, 29, 1363. (c)
Zhang, JꢀR.; Zhan, LꢀZ.; Wei, L.; Ning, YꢀY.; Zhong, XꢀL.; Lai, JꢀX.; Xu, L.; Tang, RꢀY. MetalꢀFree
Thiolation of Imidazopyridines with Functionalized Haloalkanes using Elemental Sulfur. Adv. Synth.
Catal., 2018, 360, 533.
(18) (a) Hill, C. L. Homogeneous Catalysis ꢀ Controlled Green Oxidation. Nature 1999, 401, 436. (b)
Bäckvall, J.ꢀE. Modern Oxidation Methods, WileyꢀVCH, Weinheim 2004. (c) Piera, J.; Bäckvall, J.ꢀE.
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 19
Catalytic Oxidation of Organic Substrates by Molecular Oxygen and Hydrogen Peroxide by Multistep
Electron Transfer ꢀ A Biomimetic Approach. Angew. Chem., Int. Ed. 2008, 47, 3506. (d) Shi, Z.; Zhang,
C.; Tang, C.; Jiao, N. Recent Advances in TransitionꢀMetal Catalyzed Reactions using Molecular
Oxygen as the Oxidant. Chem. Soc. Rev. 2012, 41, 3381. (e) Allen, S. E.; Walvoord, R. R.;
PadillaꢀSalinas, R.; Kozlowski, M. C. Aerobic CopperꢀCatalyzed Organic Reactions. Chem. Rev. 2013,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13, 6234.
19) For reviews of the flavin catalysts, see: (a) Imada, Y.; Naota, T. Flavins as Organocatalysts for
(
Environmentally Benign Molecular Transformations. Chem. Rec. 2007, 7, 354. (b) Gelalcha, F. G.
Heterocyclic Hydroperoxides in Selective Oxidations. Chem. Rev. 2007, 107, 3338. (c) de Gonzalo, G.;
Fraaije, M. W. Recent Developments in FlavinꢀBased Catalysis. ChemCatChem 2013, 5, 403. (d)
Cibulka, R. Artificial Flavin Systems for Chemoselective and Stereoselective Oxidations. Eur. J. Org.
Chem. 2015, 2015, 915. (e) Iida, H.; Imada, Y.; Murahashi, S.ꢀI. Biomimetic FlavinꢀCatalysed
Reactions For Organic Synthesis. Org. Biomol. Chem. 2015, 13, 7599.
(20) For examples of the flavinꢀcatalyzed aerobic oxidations mimicking the functions of
flavinꢀdependent monooxygenases, see: (a) Imada, Y.; Iida, H.; Ono, S.; Murahashi, S. I. Flavin
Catalyzed Oxidations of Sulfides and Amines with Molecular Oxygen. J. Am. Chem. Soc. 2003, 125,
2
868. (b) Imada, Y.; Iida, H.; Murahashi, S.ꢀI.; Naota, T. An Aerobic, Organocatalytic, and
Chemoselective Method for BaeyerꢀVilliger Oxidation. Angew. Chem., Int. Ed. 2005, 44, 1704. (c)
Imada, Y.; Iida, H.; Naota, T. FlavinꢀCatalyzed Generation of Diimide: An Environmentally Friendly
Method for the Aerobic Hydrogenation of Olefins. J. Am. Chem. Soc. 2005, 127, 14544. (d) Chen, S.;
Foss, F. W. Jr. Aerobic Organocatalytic Oxidation of Aryl Aldehydes: Flavin Catalyst Turnover by
Hantzsch’s Ester. Org. Lett. 2012, 14, 5150. (e) Kotoučová, H.; Strnadová, I.; Kovandová, M.;
Chudoba, J.; Dvořáková, H.; Cibulka, R. Biomimetic Aerobic Oxidative Hydroxylation of Arylboronic
Acids to Phenols Catalysed by a Flavin Derivative. Org. Biomol. Chem. 2014, 12, 2137.
ACS Paragon Plus Environment
18

Page 19 of 19
The Journal of Organic Chemistry
(
21) Ishikawa, T.; Kimura, M.; Kumoi, T.; Iida, H. Coupled FlavinꢀIodine Redox Organocatalysts:
1
2
Aerobic Oxidative Transformation from NꢀTosylhydrazones to 1,2,3ꢀThiadiazoles. ACS Catal. 2017, 7,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4986.
(
22) Ohkado, R.; Ishikawa, T.; Iida, H. Flavin–Iodine Coupled Organocatalysis for the Aerobic
Oxidative Direct Sulfenylation of Indoles with Thiols under Mild Conditions. Green Chem. 2018, 20,
84.
23) Sakai, T.; Kumoi, T.; Ishikawa, T.; Nitta, T.; Iida, H. Comparison of RiboflavinꢀDerived
Flavinium Salts Applied to Catalytic H O Oxidations. Org. Biomol. Chem. 2018, 16, 3999.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
(
2
2
(
24) The results on the optimization of solvents were summarized in Table S1 of Supporting
Information.
25) For examples of flavinꢀcatalyzed aerobic oxidation of thiols, see: (a) Gascoigne, I. M.; Radda, G.
(
K. The Chemistry of Flavins and Flavoproteins III. The Reaction of Dihydrolipoic Acid with Flavins.
Biochim. Biophys. Acta, Bioenerg. 1967, 131, 498. (b) Gibian, M. J.; Winkelman, D. V. The Oxidation
of Mercaptans by Flavins. Tetrahedron Lett. 1969, 10, 3901. (c) Loechler, E. L.; Hollocher, T. C.
Mechanism of the Reaction of Dithiols with Flavins. J. Am. Chem. Soc. 1975, 97, 3235. (d) Yokoe, I.;
Bruice, T. C. Oxidation of Thiophenol and Nitroalkanes by an Electron Deficient Isoalloxazine. J. Am.
Chem. Soc. 1975, 97, 450. (e) Yano, Y.; Nakazato, M.; Ohya, E. Substituent and Steric Effects of Flavin
Models in the Reactions of NꢀBenzylꢀ1,4ꢀdihydronicotinamide, Butaneꢀ1,4ꢀdithiol, Phenylhydrazine,
and Nitroethane. J. Chem. Soc. Perkin Trans. II 1985, 77. (f) Li, W.ꢀS.; Zhang, N.; Sayre, L. M.
1
10
N ,N ꢀEthyleneꢀBridged HighꢀPotential Flavins: Synthesis, Characterization, and Reactivity.
Tetrahedron 2001, 57, 4507.
(26) Müller, F.; Donald, B. M.; Lemuel, D. W. [147] Synthesis of 2ꢀSubstituted Riboflavin Analogs.
Methods Enzymol., 1971, 18, 453.
ACS Paragon Plus Environment
19